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Leadership Perspective: Dr David Reynolds, Chief Scientific Officer, Alzheimer’s Research UK

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Perspectives from Leaders in Neuroscience

Interview with Dr David Reynolds – Chief Scientific Officer, Alzheimer’s Research UK

Alzheimer’s Research UK is the United Kingdom’s leading dementia research charity, founded in 1992 as the Alzheimer’s Research Trust. It is dedicated to funding scientific studies to find ways to treat, cure or prevent Alzheimer’s disease, vascular dementia, Lewy body disease and frontotemporal dementia.

Coulter:Pulse recently interviewed David Reynolds, Chief Scientific Officer of Alzheimer’s Research UK, to learn more about the important role that this leading UK charity is playing in the field of Alzheimer’s research and to gain some insights into the advances that are being made to combat neurodegenerative disorders such as dementia.

David worked in the pharmaceutical industry for 18 years at Merck Sharp & Dohme, Lundbeck and latterly Pfizer where he was the Cambridge Neuroscience & Pain Research Site Head. He has held a variety of R&D leadership roles with responsibilities ranging from exploratory biology to drug discovery, early clinical development and business development in multiple disease areas, but with a focus on neuroscience and pain.

Coulter:Pulse – Please could you give us some insights into the advances that are currently being made in Alzheimer’s research?

David – Dementia research has seen renewed vigour in the last 5 to 10 years and by “dementia” I mean the full range of neurodegenerative disorders whose manifestations include a decline in memory, thinking and reasoning ability. This upturn is owed in part to increased funding but also to significant large-scale genetic studies: the genome-wide association studies or GWAS. These studies look at 50,000 to 100,000 people to identify gene mutations that indicate not that an individual will definitely develop the disease but rather indicate an increased risk of their getting the disease. An example is ApoE4, one of several variants of the apolipoprotein E (ApoE) gene which plays a role in how cholesterol is metabolized. Those who have the ApoE4 gene are three to eight times more likely to develop Alzheimer’s disease than those who do not carry ApoE4. These are risk genes rather than familial or autosomal dominant inherited genes.

GWAS have identified some 22 to 25 risk genes which point to new potential areas of research into the core processes of neurodegeneration that may have been under-investigated until now. These include the ways in which we handle energy and metabolism. The brain uses a great deal of energy and the way neurons handle this is important. How we make proteins, the quality control processes around this and how we dispose of those we don’t want anymore are all critical factors. If something goes wrong, there is a build-up or aggregation of protein – a hallmark feature found in the brain of someone who has died of dementia. You may have heard of amyloid plaques and tau tangles? These accumulations of amyloid proteins or tau proteins share a common core process and what we’ve discovered across a whole range of neurodegenerative disorders is that protein aggregation is critical and underpins many of them

The Immune system

Another key focus of research is the role of the immune system. The brain has historically been considered an immune privileged organ, meaning that it does not have a strong inflammatory immune response when challenged. What we have now appreciated, however, is that the brain has its own resident immune cells, microglia, which play a much more important role in the disease processes than was once thought. In the case of neuroinflammation, the immune system may act beneficially at a certain point and provide a defence mechanism, but at other points it is probably overactive and contributes to the problem. Unpicking which parts of the immune system have an influence, at which points in the disease and in which patients, is a key area of research and offers a great opportunity in this space for potential treatments. When we understand this aspect of the brain and immune system more fully, we may be able to find shortcuts to new medicines for dementia by repurposing some of the many drugs which already target the immune system for peripheral disorders.

Our understanding is improving all the time and what I hope I have illustrated is that new avenues have opened and have reinvigorated dementia research. This research had become very amyloid and tau centric and, while both are important areas of focus in Alzheimer’s disease, they are not the only ones to consider. Mutations in these genes – amyloid and tau – can lead to autosomal dominant neurodegeneration. This form of Alzheimer’s disease is usually developed in the thirties, forties and fifties rather than the seventies and eighties. Genetically inherited forms of the disease receive a great deal of media coverage but account for less than 1% of total Alzheimer’s cases. While they have been the main model used to help researchers understand Alzheimer’s disease, genetic studies of the general population have opened up many new avenues to explore.

Coulter:Pulse – How do the recently widely publicised Trazodone and DBM trials fit into this picture?

David – This research has had quite extensive media coverage. It came out of university laboratories and is all to do with the protein synthesis and degradation pathway I talked about earlier. We know that when cells are under stress, they can decrease their rate of protein synthesis. Alzheimer’s patients have chronically reduced levels of protein synthesis but making new proteins is critical for keeping nerve cells working properly. The aim of the research was to find drugs which could increase protein synthesis and then establish whether this could be beneficial. Around 1000 approved drugs (and, in the case of DBM, a product currently in development) were screened to find out if they increased protein synthesis. Researchers followed up on two of these with a mouse study. Mice were infected with a prion disease (which can cause CJD), an infectious disease, or a type of genetic dementia, both of which cause neurodegeneration. Later they were treated with either trazodone hydrochloride, a drug used to treat depression, or dibenzoylmethane, a drug currently being trialled as an anti-cancer compound.

This promising early stage experimental research demonstrated a beneficial neurological effect of trazodone and dibenzoylmethane on mice with diseases mimicking neurodegenerative diseases. Both drugs restored memory, reduced signs of neurodegeneration and were safe for the mice in the doses given. It is important to recognize, however, that this is animal research and therefore the drugs might not have the same effect when they are trialled on humans. Trazodone is nevertheless already an approved drug for depression and sleep problems and has therefore already passed safety tests. If the mechanisms of neurodegeneration in humans and mice are similar, it is possible trazodone could be used in the future in treating Alzheimer’s and other neurodegenerative diseases. These drugs will need to be proven effective and safe in people with neurodegenerative diseases before becoming available.

Gene Therapy

Let me explain why in Alzheimer’s disease gene therapy is very difficult. In the case of Parkinson’s disease, another neurodegenerative disorder, the main pathology is that dopaminergic neurons degenerate – these neurons project to an area of the brain called the striatum and are important for controlling movement. It is not the only form of neuronal loss in Parkinson’s disease but it is by far and away the cardinal feature. For Parkinson’s disease, gene therapy has been trialled and cells that produce dopamine have been implanted in the striatum to replace what has been lost. In the future, dopaminergic cells could potentially be transplanted into the area where the cell bodies are in the substantia nigra and regrow their processes. This is achievable because there is one discrete lesion; one type of cell in part of the brain goes wrong and leads to the disease.

By contrast, Alzheimer’s disease starts in one part of the cortex but by the time major symptoms appear, it is all over the brain. An educational video about Alzheimer’s disease on the ARUK website shows that a late stage Alzheimer’s brain is about 140 grams lighter than an age-matched control. Our public awareness video drives home two important points: firstly, it illustrates what Alzheimer’s does to the brain and, secondly, it explains that dementia is a disease or caused by diseases and not just an inevitable part of ageing. It physically attacks the brain and a large mass of matter is lost. This mass is not all in one place, however, but is diffuse across the entire brain and this makes it difficult to target by gene therapy.

Video link:

Coulter:Pulse – Could you outline some of the key challenges ARUK is facing and the role you are playing in overcoming these?

David – The key challenge for a long time has been lack of investment. Through the Prime Minister’s global Challenge on Dementia, launched by David Cameron at the G8 summit in 2013, a great deal of political focus has been directed to this area. This in turn has helped attract various forms of funding, increased public awareness and generated more attention in the NHS. There is now an improving picture of funding for dementia research but it’s coming from a very low base line and is still a tiny fraction of what goes into cancer research. The biggest problem in dementia research for the Life Science industry is that there has been no new treatment launched for Alzheimer’s disease or any other dementia since 2002. 15 years have gone by in which we have greatly improved our understanding of dementia, but haven’t been able to translate this into new treatments.

There has been significant pharmaceutical company investment, but these are businesses not charities and are looking for a return on their investment. When companies look at therapeutic areas to invest in, they want to know the extent of the medical need, what a drug could deliver and what money they can make. At zero percent success, any risk, time and cost analysis does not look at all favourable. Many companies have either pulled out completely or scaled back. While some like Biogen are still in the race, hoping to be one of the first companies with disease-modifying therapies on the market, they have inevitably become more risk averse, knowing the chance of success is so much lower than in other therapeutic areas. They are much less willing to invest in early stage exploratory research and would rather wait until someone has de-risked the situation first.

Alzheimer’s Research UK and the Dementia Research Institute 

In this landscape, how can a charity like ours fit in? Firstly, we can fund research that helps drive our knowledge base. The flagship example of this is the Dementia Research Institute which was announced last year. This £250 million project received £150 million from the government under David Cameron’s 2020 Challenge on Dementia which was channelled through the Medical Research Council. The project received a further £50 million from ARUK and another £50 million from Alzheimer’s Society. The distributed model has centres at UCL, Kings, Imperial, Cambridge, Edinburgh and Cardiff.

Secondly, we have the sort of expertise that is critical to make things happen. Quite unusually for a charity, Alzheimer’s Research UK has people who understand the different parts of the ecosystem in depth and know how to work closely with pharmaceutical companies and academicians alike to advance from an idea to a medicine. In 2015, we launched a drug discovery alliance with a £30 million investment over 5 years in three flagship Drug Discovery Institutes at the Universities of Cambridge and Oxford and UCL. We take the great science that comes out of academic laboratories and de-risk the list of un-validated targets into a shorter list of validated targets that industry can pick up and run with. What industry does well, once the target is known, is make a drug, test it in the clinic and get it on the market. What they’re not so good at – and no longer have the infinite funds to do – is the early stage research to sift through all the options and define which ones are likely to work. Our role is at that early stage, where we try and repeat what has already been done, and then find molecules that are potent, selective and essentially effective in animal models and cell-based models of the disease.

 

Inevitably, there are obstacles along the way and we have had to abandon one project because we couldn’t repeat anything that was in the literature that suggested it was a good choice. Although that’s disappointing, it is also useful in refining the potential candidate list. Through the Drug Discovery Alliance, we take early stage research and do those first translational steps. Most importantly, this is not academic drug discovery but rather professional drug discovery in an academic environment. What I mean by that is that CSOs have been hired who are the heads of each of these institutes, the heads of chemistry and heads of biology, all with industry experience. They know what the customer – in this case pharmaceutical companies, biotechs, or VC investors – wants and they know how to package the solution to look attractive. This is a valuable skill and not one generally to be found in academics, who are more invested in the scientific endeavour of finding out what causes the disease to work as it does.

Coulter:Pulse – Attracting the right talent and leadership must be very important to your success in achieving the goals of Alzheimer’s Research UK?

David -Talent is critical to our success in all of this. For the kinds of investment the charity wants to make, we need to understand everything from the very early basic research going on in an academic lab through to what we are actually trying to do in the drug discovery, lead development, candidate selection and clinical trial landscape. And when we get to the end stage, how do market dynamics, pricing and access work? Because if we want to lobby government to change things, we need to understand what’s going on at that end too.

Essentially, we need to have the broadest knowledge and skillset possible. Having spent 20 years in the industry, I have worked at the exploratory coalface, in early stage clinical trials, and have been part of teams with commercial insight of why an area is not attractive even though there are huge numbers of patients. Understanding what makes a profitable drug, what challenges we face in the marketplace with healthcare providers, how to access patients, and the myriad of practical issues can all be critical to success. If a patient is very frail and can’t swallow the pills or administer a drug, for instance, this can have important consequences. The antibody drugs which may be the first to hit the market for dementia could be delivered as a monthly IV infusion to potentially frail elderly patients. IV infusions carry risk of infection, it’s difficult to find veins in some older patients and many other challenges exist. How well is the Health Service set up to provide monthly IV infusions to 850,000 patients?

I need to have a broad understanding of the full spectrum of the charity’s activity, supported by others who understand different areas in depth. We need the skills to best direct the limited funds in the most effective manner and to lobby government to help plan for the challenges ahead. The same goes for drug discovery institutes; we need people running them who know what drug discovery looks like – for instance, how to make an assay fit for purpose for an industrial application.

Coulter:Pulse –  How difficult is it to find people with these sorts of skills and attract them to this area?

David – Large Life Science companies have released many highly-experienced people into the market over the years but, in the next 10 to 15 years, people with such extensive experience and an end-to-end view of drug discovery will not be coming through in the same numbers. This is of great concern to the ABPI and the Association of Medical Research Charities and, because many big pharma companies have now also scaled back the number of industrial sandwich year placements for students, training the next generation is becoming quite a challenge.

Coulter:Pulse – I expect that whole landscape is becoming quite difficult too following the Brexit referendum?

The UK has always attracted strong international talent from Europe and elsewhere because it punches well above its weight in academic and industrial science. Nevertheless, the current climate of uncertainty is having a discernible impact on our own recruitment for the Dementia Research Institute. This uncertainty is also beginning to deter large global companies from investing in the UK.

Alzheimer’s Research UK’s strategy in the past few years has seen us increasingly looking around the world for new approaches to tackling dementia and partnering with likeminded innovators. Initiatives like the Dementia Consortium and the ARUK Drug Discovery Alliance have pioneered collaborative approaches to research that unite academy, industry and biotech in a common desire to make better and swifter progress towards the next treatment.

Another project at international level has been TheDementia Discovery Fund, a venture capital fund managed by SVLS that was launched in 2015 as part of the Prime Minister’s global Challenge on Dementia. The collaborative initiative, designed to speed up the development of new treatments for dementia, has secured $100m backing from worldwide investors including the UK Government’s Department of Health, Alzheimer’s Research UK and several pharmaceutical companies. The classic VC fund can only invest in dementia, typically an area that doesn’t attract venture capital because the risk is so high and return on investment is further away than usual. Very few VC-funded biotechs have set up in this area so it is designed to address this issue. ARUK’s Drug Discovery Alliance may take a molecule to a certain stage and then it might be the DDS that funds it onwards to sell to a large pharma company who will take it all the way through to the market.

Coulter:Pulse – What do you see as the most promising advances in the field of neurogenerative disorders generally?

David – What we have learnt through genetic studies into Alzheimer’s disease and many other diseases is that there are more common underpinnings of the disease mechanism than there are differences. Having advanced from the post-mortem hallmark features of a brain to the molecular pathways of this, we have understood that protein synthesis and degradation is core to all of them. I think that over time this will accelerate drug discovery in some of the rare forms of dementia and other neurodegenerative diseases because we’ll find a convergence of disease processes.

It may well be that, if we can target these processes, we can then get drugs that have an element of broad-spectrum neurodegenerative therapy rather than just working for X or for Y.

Coulter:Pulse – Please could you tell us about some of the defining moments in your own career in Life Sciences?

David – I was extremely fortunate when studying for my PhD to work at Glaxo’s Institute of Applied Pharmacology in Cambridge. This was the first of its kind – a partnership of industry and academia where Glaxo scientists worked in the Department of Pharmacology together with academic researchers. I came to understand that pharmaceutical research was not the dark side! It gave me an early appreciation of how industry works in relation to academia and the challenges that are unique to both worlds in translating quality science into medicines for patients. As a consequence, I then went into industry as an in vivo scientist.

Around 2007 when jobs were becoming more scarce, I decided to broaden my skillset in biomarkers and business development within Pfizer and worked in various disease areas. I became part of the senior leadership team at Neusentis and, ultimately, Site Head. In 2016 I decide it was time for a new direction. I wanted to make a more positive and long-term contribution to patient benefit than the short-term thinking of pharma could accommodate. Within a charity, I felt I could control my own destiny and see a project through to definable goals more effectively

How do we get to a solution via diagnostics that can be used at population level? How do we find out among the plethora of technology offerings which are the ones that could ultimately make an enormous difference to global health? This is where the charity can achieve a great deal through long-term investment and achieve real gains for patients. Although it’s a charity that’s been around for 25 years, in the last 5 years Alzheimer’s Research UK has grown beyond all recognition thanks to enthusiastic and talented senior leadership that has driven 20% year-on-year growth and launched many significant initiatives. I wanted to be part of that. I joined a year ago and am absolutely loving it!

My talents are being put to good use at ARUK and I’m learning all the time. Fundraising and media skills are just two of many new areas of expertise I am now mastering. Biogen had a paper published last year on aducanumab antibodies so I suddenly found myself on the BBC Breakfast sofa. Above all, I am learning to communicate science with clarity and make it accessible to non-scientists.

Awareness of dementia has probably never been higher in fact, but understanding of dementia is still woefully inadequate. When we run surveys, only 23% of the population identify dementia as being caused by disease. Most still think it’s an inevitable part of ageing. My key message is that research has beaten diseases in the past and it will do again – with time, effort and money, we can beat dementia.

 
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